Human immunodeficiency virus (HIV) infection is associated with several different clinical syndromes including immunosuppression, Kaposi's sarcoma, wasting syndrome, and neurological abnormalities such as dementia. The goal of this project is to understand the role of variation in the viral genes in causing these diverse syndromes. We recently showed that HIV strains with ability to infect macrophages shared a strong homology in the amino acid sequences of their envelope proteins in the hypervariable V3 region. Other work has now confirmed that such macrophage-tropic HIV strains appear to be the main ones sexually transmitted between different individuals. The wide diversity of V3 sequences seen at later disease stages appears to evolve independently in each infected individual. Thus, the macrophage-tropic envelope consensus sequence may be an ideal target to which potential vaccines should be directed. In more recent studies we have analyzed V3 envelope sequences from a group of AIDS patients with and without HIV dementia. Whereas brain derived HIV from both groups appeared to be closely related to macrophage-tropic HIV strains, viruses from demented patients showed significant differences from those from non-demented patients. These results suggested that HIV dementia might be caused by a unique subset of macrophage-tropic HIV strains. The ability of primary AIDS patient HIV isolates and laboratory-adapted HIV isolates to infect cells in vitro was studied using HeLa-CD4 clones expressing differing amounts of CD4. Laboratory-adapted HIV showed a similar level of infectivity over a wide range of CD4 expression. In contrast, infectivity of primary patient HIV isolates was directly proportional to the amount of CD4 expressed on HeLa cells. These results demonstrate important functional differences in the envelope genes of primary patient HIV isolates which could be involved in various in vivo pathogenic effects.